Catherine Watson

Treatment of patients with cardiovascular disease with L-4F, an apo-A1 mimetic, did not improve select biomarkers of HDL function.

L-4F, an apolipoprotein A-I (apoA-I) mimetic peptide (also known as APL180), was administered daily by either intravenous (IV) infusion for 7 days or by subcutaneous (SC) injection for 28 days in patients with coronary heart disease in two distinct clinical studies. L-4F was well tolerated at all doses tested. Despite achieving plasma levels (mean maximal plasma concentration of 2,907 ng/ml and 395 ng/ml, following IV infusion and SC injection, respectively), that were effective in previously published animal models, treatment with L-4F, as assessed by biomarkers of HDL function such as HDL-inflammatory index (HII), and paraoxonase activity, did not improve. Paradoxically, there was a 49% increase in high-sensitivity C-reactive protein (hs-CRP) levels after seven IV infusions of 30 mg L-4F (P < 0.05; compared with placebo) and a trend for hs-CRP increase in subjects receiving 30 mg SC injection for 28 days. In a subsequent, ex vivo study, addition of L-4F at concentrations of 150, 375, or 1,000 ng/ml to plasma from subjects prior to L-4F treatment resulted in significant dose-dependent HII improvement. In conclusion, in vivo L-4F treatment, delivered by either SC injection or IV infusion, did not improve HDL functional biomarkers despite achieving plasma levels that improved identical biomarkers ex vivo and in animal models.

LCI699, a potent 11β-hydroxylase inhibitor, normalizes urinary cortisol in patients with Cushing's disease: results from a multicenter, proof-of-concept study.

INTRODUCTION The clinical features and increased mortality associated with Cushings syndrome result from a chronic excess of circulating cortisol. As LCI699 potently inhibits 11β-hydroxylase, which catalyzes the final step of cortisol synthesis, it is a potential new treatment for Cushings disease, the most common cause of endogenous Cushings syndrome. METHODS Adult patients with moderate-to-severe Cushings disease (urinary free cortisol [UFC] levels >1.5 × ULN [upper limit of normal]) received oral LCI699 for 10 weeks in this proof-of-concept study. LCI699 was initiated at 4 mg/d in two equal doses; the dose was escalated every 14 days to 10, 20, 40, and 100 mg/d until UFC normalized, whereupon the dose was maintained until treatment ended (day 70). The primary endpoint was UFC ≤ ULN or a ≥50% decrease from baseline at day 70. RESULTS Twelve patients were enrolled and completed the study. Baseline UFC ranged over 1.6-17.0 × ULN. All 12 patients achieved UFC ≤ULN or a ≥50% decrease from baseline at day 70; 11 (92%) had normal UFC levels at that time. After treatment discontinuation (day 84), UFC was >ULN in 10 patients with available measurements. Mean 11-deoxycortisol, 11-deoxycorticosterone, and adrenocorticotropic hormone levels increased during treatment and declined after discontinuation. Mean systolic and diastolic blood pressure decreased from baseline by 10.0 and 6.0 mmHg, respectively. LCI699 was generally well tolerated; most adverse events (AEs) were mild or moderate. The most common AEs included fatigue (7/12), nausea (5/12), and headache (3/12). No serious drug-related AEs were reported. CONCLUSIONS LCI699 was efficacious and well tolerated in patients with Cushings disease enrolled in this proof-of-concept study.

HORMONAL AND ELECTROLYTE RESPONSES TO THE ALDOSTERONE SYNTHASE INHIBITOR LCI699 IN SODIUM DEPLETED HEALTHY SUBJECTS

Results: LCI699 was well tolerated following both single (0.5-200 mg) and multiple (0.5-10 mg) doses. LCI699 was rapidly absorbed (Tmax 1 h) and demonstrated linear, dose-overproportional pharmacokinetics with an elimination half-life of ~4 h. After the first dose, plasma aldosterone (AUC 0-12 h) decreased dose dependently (35-41%). After 7 daily doses of LCI699 (1-10 mg), 24 h urinary aldosterone decreased by 22-83% and plasma aldosterone by 27-44%. In contrast, eplerenone increased urinary and plasma aldosterone by 88% and 38%, respectively. On Day 1 of treatment, LCI699 increased sodium excretion to a similar extent as eplerenone (~60-110%). All LCI699 doses and eplerenone resulted in small (0.2-0.4 mmol/L), transient increases in plasma potassium which returned to placebo levels by Day7. Signs of hypoaldosteronism (postural tachycardia, decreased body weight and mild hyponatremia) were detected in some subjects at the 3 mg qd dose. Aldosterone inhibition by LCI699 (0.5-3 mg) was accompanied by a dose-dependent increase in trough plasma renin activity from 90-287% on Day 7 compared with eplerenone (56%).

Discovery of N-[5-(6-Chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-ethanesulfonamide, a Cortisol-Sparing CYP11B2 Inhibitor that Lowers Aldosterone in Human Subjects.

Human clinical studies conducted with LCI699 established aldosterone synthase (CYP11B2) inhibition as a promising novel mechanism to lower arterial blood pressure. However, LCI699s low CYP11B1/CYP11B2 selectivity resulted in blunting of adrenocorticotropic hormone-stimulated cortisol secretion. This property of LCI699 prompted its development in Cushings disease, but limited more extensive clinical studies in hypertensive populations, and provided an impetus for the search for cortisol-sparing CYP11B2 inhibitors. This paper summarizes the discovery, pharmacokinetics, and pharmacodynamic data in preclinical species and human subjects of the selective CYP11B2 inhibitor 8.

Vildagliptin does not affect C-peptide clearance in patients with type 2 diabetes.

V is a potent and selective inhibitor of dipeptidyl peptidase-IV (DPP-4) being developed for the treatment of type 2 diabetes (T2DM). Dipeptidyl peptidase-IV is the enzyme that degrades and inactivates the gastrointestinal hormone, glucagonlike peptide-1 (GLP-1). Glucagon-like peptide-1 can exert multiple beneficial metabolic effects, including glucose-dependent stimulation of insulin secretion, suppression of glucagon secretion, reduction of insulin resistance, and suppression of glucose production. Therefore, inhibiting the degradation of endogenous GLP-1, thereby increasing plasma levels of intact, biologically active GLP-1, holds considerable therapeutic promise. Indeed, vildagliptin has been shown to improve glycemic control in patients with T2DM, when given as monotherapy or in combination with metformin. Given the known effects of GLP-1 to stimulate insulin secretion, it was of interest to characterize the effects of vildagliptin on the insulin secretory rate (ISR) in patients with T2DM. Deconvolution of plasma C-peptide levels is a well-established and accepted methodology to quantify ISR. However, this approach relies on standard parameters of C-peptide clearance and assumes that any agent being tested does not influence this process. Because DPP-4 cleaves the N-terminal 2 amino acids from peptides with a proline or an alanine in the penultimate position and because human C-peptide (like GLP-1) has an alanine in position 2 (ie, alanine is the N-terminal penultimate amino acid in C-peptide), it was possible that a DPP-4 inhibitor such as vildagliptin could exert acute effects on the clearance of C-peptide. Therefore, the purpose of the current work was to evaluate effects of vildagliptin on C-peptide clearance in patients with T2DM. Toward that end, plasma C-peptide levels were measured over a 24-hour period, including 3 standardized meals, before and on the first day of treatment with vildagliptin (100 mg, bid) in drug-naive patients with T2DM. The overall objective of the study (published previously) was to assess the effects of 28-day treatment with vildagliptin on β-cell function, as quantified by mathematical modeling of the insulin secretory rate, as described by Mari and colleagues. However, the present report focuses on the potential acute influence of vildagliptin on C-peptide clearance on the first day of treatment—a time at which minimal effects on plasma glucose were expected. A lack of effect of vildagliptin is needed to be able to reliably estimate the insulin secretion rate by deconvolution of endogenous C-peptide concentrations using standard parameters during vildagliptin treatment.

Lack of effect of LAF237 on C-peptide clearance in patients with type 2 diabetes

LAF237 is potent DPP‐4 inhibitor and under development as an oral anti‐diabetic agent. It is expected to stimulate glucose‐dependent insulin secretion. Deconvolution of C‐peptide (C‐Pep) levels is used to estimate insulin secretion rates (ISR).1 The objective of the present work was to assess the effect of LAF237 on C‐pep clearance (CL) in patients with type 2 diabetes (T2D).